This invention is in the field of improving the tolerability of daunorubicin and reducing the toxicity or adverse drug reactions in noncancerous tissues by producing the orotate salt of daunorubicin. Daunorubicin hydrochloride (cerubidine) is a hydrochloride salt of an anthracycline antibiotic produced by a strain of Streptomyses coeruleorubidus. It is provided as a sterile reddish lyophilized powder in vials for intravenous administration only. It was initially isolated from Streptomyces peucetius. A liposomal formulation of daunorubicin is marketed as DaunoXome. Daunorubicin hydrochloride slows or stops the growth of cancer cells in the body. It is most commonly used in pediatric and adult patients to treat specific types of leukemias, for example acute myeloid leukemia and lymphocytic leukemia. Treatment is usually performed together with other chemotherapy drugs such as cytarabine, and its administration depends on the type of tumor and the degree of response. Because of its use in pediatric patients it is very important to monitor the serious toxicities associated with daunorubicin hydrochloride. Daunorubicin hydrochloride is also used as the starting material for semi-synthetic manufacturing of doxorubicin, epirubicin and idarubicin.
Mode of Action—daunorubicin binds to DNA and intercalates, with its daunosamine residue directed toward the minor groove. It has the highest preference for two adjacent G/C base pairs flanked on the 5′ side chain by an ATT base pair. Daunomycin effectively binds to every 3 base pair and induces a local unwinding angle of 11° but negligible distortion of the helical conformation.
Route of Administration—daunorubicin should be administered in a rapid infusion. It should not be administered intramuscularly or subcutaneously since it may cause extensive tissue necrosis. It should never be administered intrathecally (into the spinal cord) as this will cause extensive damage to the nervous system and may lead to death. Mortensen M E et al, 1992, Med Pediatric Oncol 20: 249-253. It has been established that the use of liposomes for the administration of anti-neoplastics in many cases improves the traditional methods of administration. Gabizon, Cancer Res. (1992), 52; 891-896 and Van Hossel et al, Cancer Res (1984) 44; 3698-3705. Different patents describe the inclusion of anti-free radical agents into liposomes having improved activity as inhibitors of lipid peroxidation. U.S. Pat. No. 5,605,703, issued Feb. 25, 1997. Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. In addition, different liposomal drug products may vary from one another in the chemical composition and physical form of liposomes. Such differences can substantially affect the functional properties of liposomal drug products. A liposomal formulation is marketed in the United States as DaunoXome.
Cardiac Toxicity—The cardiac toxicity exhibited by daunorubicin hydrochloride and the other anthracyclines is unique in terms of its pathology and mechanism. The major limiting facts in the clinical use of anthracylclines in adults are bone marrow suppression, mucositis, and drug resistance on the part of the tumor. Myocardial toxicity manifests in its most severe form by potentially fatal congestive heart failure and may occur either during therapy or months to years after termination of therapy. Children seem to be more sensitive to the cardiac toxicity of this drug, and this has become a significant problem in the use of daunorubicin in pediatric oncology. Management of Drug Toxicity, Ch 31-42, in The Chemotherapy Source Book, 3rd ed, Michael C. Perry, Lippincott Williams & Wilkins, 2001.
Thus there is a great need for analogues which give a better rate of response, a wider spectrum of response, and/or reduce cardiotoxicity. Much of the history and prior art of adriamycines are found in issued patents and published literature. U.S. Pat. No. 5,304,687 issued Apr. 19, 1994; U.S. Pat. No. 5,605,703 issued Feb. 25, 1997; U.S. Pat. No. 6,210,930 issued Apr. 3, 2001; U.S. Pat. No. 6,284,737 issued Sep. 4, 2001; and U.S. Pat. No. 6,653,455 issued Nov. 25, 2003.
However, the present invention is distinguishable from the prior art because none of the prior art addresses the issue of reducing the toxicity and adverse drug reactions in normal animals. More tolerable and less toxic agents are widely sought and are a fundamental object of the invention. The pertinent subject matter of the above references is specifically incorporated herein by reference.